Metal complex-containing pharmaceutical agents

ABSTRACT

Improved metal complex-containing pharmaceutical agents are described which, as an additive, contain one or more complexing agents and/or one or more weak metal complex(es) or mixtures thereof.

BACKGROUND OF THE INVENTION

[0001] This invention relates, e.g., to improved agents basedmetal-containing complex compounds suitable for NMR, X-ray, ultrasoundand radiodiagnosis and therapy and a process for their production.

[0002] Soon after the discovery of X-rays the most varied substanceswere experimentally tested as “contrast media” to boost the insufficientcontrast of body fluids and soft tissues (Barke, R.Roentgenkontrastmittel [X-ray Contrast Media]; Chemie, Physiologie,Klinik VEB Georg Thieme Leipzig, 1970). Heavy elements were suitable asthe X-ray absorbing elements of such contrast media. In the course of along selection and optimization process, finally only contrast mediabased on iodine (in a stable organic bond) or barium (as a nearlyinsoluble sulfate) remained. Barium sulfate is used exclusively forvisualization of the gastro-intestinal tract and it does not penetratethe body.

[0003] With the development of nuclear medicine, e.g., the use ofradioactive elements for visualizing certain structures of the organismand pathological areas and especially for functional diagnosis and forradiotherapy, a series of other metals was accepted for in vivodiagnosis. The so-called radiopharmaceuticals used in nuclear medicinecontain either a radioactive isotope of iodine (¹³¹I or ¹²³I) orpreferably a metal such as ^(99m)technetium. These elements are bondedto an organic substance in many cases or, in the case of the radioactivemetal isotope, are administered in complexed form. Most often, thestability of the complexing of the metals is such that, during its stayin the body, a more or less large portion of the metal cannot beprevented from being released from its bond to the organic molecule.Thus, in general, the metal ion loses its desired pharmacokinetic anddiagnostic properties produced by the complexing, is eliminated onlyvery slowly, disturbs the distribution picture, specific in itself, ofthe isotope that is still bonded and can exhibit its inherently toxicproperties.

[0004] At the beginning of the 1980s the interest in metal complexes indiagnostics and therapy increased further. With the development ofnuclear spin tomography there arose the question of producing contrast,e.g., signal-influencing substances that could be introduced into thebody from the outside. Such substances help to recognize diseasesearlier and more accurately. As an effective principle, complexparamagnetic metal ions were introduced which, despite a relatively highdosage (e.g., several grams of complex that contain about 1-2 g of heavymetal) and rapid intravenous injection, have proven to be surprisinglywell tolerated (R. Felix, W. Schoerner, M. Laniado, H. P. Niendorf, C.Claussen, W. Fiegler, U. Speck; Radiology 156, 3: 681-688 (1985)).Especially notable is the obviously outstanding acute tolerance ofgadolinium-DTPA (European patent application 71564), the most advancedpreparation to date in clinical use. The extremely low number and themild nature of the acute side effects caused by gadolinium-DTPA make itappear suitable also for use in connection with certain X-raytechniques. The necessity of higher dosages and of repeatedadministration exists for a series of diagnostic problems in nuclearspin tomography and very generally in X-ray diagnosis. In thisconnection, the question of long-term tolerance of substances containingheavy metals must be given great attention.

[0005] Unlike the case for iodine in the iodine-containing X-raycontrast media, the central atoms in the metal-containing complexcompounds that are suitable for NMR, X-ray, ultrasound andradiodiagnosis and for therapy are not bonded covalently. The bond ofthe metal ion is subject to equilibrium with the surroundings which,according to nature, should be on the side of the complex as much aspossible. However, a permanent bond can never be attained. In additionit should be noted that the stability constants, some very high,indicated for the complexes relate to unphysiologically high pH valuesand do not apply for the in vivo situation. Further, in vivo, aconcurrence of different ions is involved in the bond to the complexingagents so that the probability for the undesired and sometimes dangerousrelease of heavy metal ions in the organism increases.

[0006] The danger becomes greater

[0007] the higher the dosage of the heavy metal complex

[0008] the more often the complex is used

[0009] the longer it remains in the body

[0010] the more chemically or metabolically unstable the complexingagent is and

[0011] the more it penetrates the cells of the body.

[0012] On the other hand, tissue-specific complexes, for example alsothose complexes bonded to biomolecules or macromolecules,, desired-fordiagnosis and radiotherapy of certain types of pathological changes areprecisely those, in comparison to gadolinium-DTPA, characterized by alonger and more intracellular stay in the body.

[0013] Thus, for diverse purposes, there is a need for better toleratedagents in which a release of the heavy metal ion in question from thecomplex compound is prevented as much as possible.

SUMMARY OF THE INVENTION

[0014] Thus, it is an object of the invention to make available such apharmaceutical agent, as well as a process for its production.

[0015] Upon further study of the specification and appended claims,further objects and advantages of this invention will become apparent tothose skilled in the art.

[0016] It has been found that adding one or more free complexingagent(s) and/or one or more weak metal complex(es) or their mixtures topharmaceutical agents based on metal complexes surprisingly yieldsunobjectionably tolerable complexes.

[0017] In this connection, the complexing agent can be identical ordifferent in all three components, i.e., in the diagnostic agent ortherapeutic agent, in the additive complexing agent, and in the additiveof a weaker metal complex. Suitable such complexing agents include, forexample, the complexing agents disclosed in patent applications EP71.564 (e.g., ethylenediaminetetraacetic acid EDTA,diethylenetriaminepentaacetic acid DTPA and many others), DE-OS 3401052(e.g., 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid DOTA,trans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid and manyothers), EP 130934 (e.g.,N⁶-carboxymethyl-N³,N⁹-[2,3-dihydroxy-N-methylpropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid and many others) and, for example,N⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid,N³,N⁶-bis(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid,N³,N⁶-bis(carboxymethyl)-N⁹[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]-3,6,9-triazaundecanedioicacid, etc. Suitable complexing agents are also disclosed in U.S. Pat.No. 4,647,447 and U.S. Ser. Nos. 936,055 of Nov. 28, 1986, 020,992 ofMar. 2, 1987, 627,143 of Jul. 2, 1984, 063,355 of Jun. 18, 1987, 078,507of Jul. 28, 1987, 100,681 of Sep. 24, 1987, and others.

[0018] Among suitable weaker metal complexes are those that have arelatively low stability constant; preferred are those that have, as acentral atom, a metal ion of elements occurring naturally in theorganism such as calcium, magnesium, zinc and iron.

[0019] The additives to be used in accordance with this invention can beroutinely selected by those of skill in the art in accordance with thisspecification. The complexing agents used as additives, as notedelsewhere, can be selected from the wide variety of complexing agentsknown to be useful chelating agents for metals, and especially fromthose disclosed as being useful in conjunction with forming metalcomplexes useful for the mentioned diagnostic or therapeutic procedures.The magnitude of the difference between the stability constants of theactive complex and the additive complex is not critical; it is importantonly that the stability constant of the additive complex be lower thanthat of the active complex. Typically, however, the difference betweenthe stability constants of the two complexes will be on the order of atleast 10².

[0020] The metal of the metal complex additive will in all cases bedifferent from the metal of the active metal complex and, as mentionedbelow, most preferably will be a physiologically well-tolerated metalsuch as one which is natural in the organism but, in all cases, willhave a biological tolerance which is greater than that of the metal perse in the active metal complex.

[0021] The complexing agents (chelating agents) and metal complexes canbe used in the form of physiologically aceptable salts of inorganic(e.g., potassium, sodium, lithium hydroxide) or organic (e.g., primary,secondary, tertiary amines such as ethanolamine, morpholine, glucamine,N-methyl, N,N-dimethylglucamine) bases, basic amino acids and amino acidamides (e.g., lysine, arginine, ornithine) or acids (e.g., glucuronicacid, acetic acid), etc., e.g., as disclosed in the documents citedabove.

[0022] The production of exemplary additives is described by thefollowing examples:

[0023] 1) Calcium-disodium salt of1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA)

[0024] 40.40 g (0.1 mol) of DOTA (Parish Chemical Comp.) is refluxedwith 10.0 g (0.1 mol) of calcium carbonate in 100 ml of water untilgeneration of gas has ended. Then, by adding 200 ml of a 1 n sodiumhydroxide solution, a neutral saline solution is produced which isevaporated to dryness in a vacuum. 50.5 g of a monohydrate is obtainedas a white powder with a decomposition point above 250° C.

[0025] Analysis (relative to an anhydrous substance): C 39.50 H 4.97 N11.52 Ca 8.24 (calculated) C 39.65 H 5.05 N 11.30 Ca 8.18 (found)

[0026] The zinc disodium salt of DOTA is obtained in an analogous wayfrom DOTA, zinc carbonate and sodium hydroxide solution.

[0027] 2.N⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

[0028] 17.9 g (50 mmol) of1,5-bis(2,6-dioxomorpholino)-3-azapentane-3-acetic acid is mixed in 50ml of water with 100 ml of an aqueous molar solution of methylamine. Itis stirred for 12 hours at room temperature and the weak, yellowsolution is bleached by filtration through activated carbon. Afterevaporation in a vacuum, 20.5 g (=98% of the theoretical) of a whitehygroscopic powder with a melting point of 78-82° C. is obtained.

[0029] Analysis (relative to an anhydrous substance): C 45.81 H 6.97 N16.70 (calculated) C 45.62 H 7.03 N 16.52 (found)

[0030] 3. a)N³-(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioicacid.

[0031] A suspension of 21.1 g (50 mmol) ofN³,N⁶-bis(carboxymethyl)-N⁹-(ethoxycarbonylmethyl)-3,6,9-triazaundecanedioicacid (J. Pharm. Sci. 68, 1979, 194) in 250 ml of acetic anhydride isstirred, after the addition of 50 ml of pyridine, for 3 days at roomtemperature. Then the precipitate is suctioned off, it is washed threetimes, each time with 50 ml of acetic anhydride and it is finallystirred up for several hours with absolute diethyl ether. Aftersuctioning off, washing with absolute diethyl ether and drying in avacuum at 40° C., 18.0 g (=89% of theory) of a white powder with amelting point of 195°-196° C. is obtained.

[0032] Analysis: C 47.64 H 6.25 N 10.42 (calculated) C 47.54 H 6.30 N10.22 (found)

[0033] b) Tetrasodium salt ofN³,N⁶-bis-(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid.

[0034] 2.42 g (6 mmol) of the compound obtained in a) is suspended in 30ml of dimethyl formamide. Then, at −5° C., 3.04 g (30 mmol) oftriethylamine and 0.52 ml (6 mmol) of morpholine are added, left at thistemperature for 2 hours, then it is further stirred overnight,evaporated in a vacuum to dryness and the residue is mixed with 100 mlof diisopropyl ether. After suctioning off and drying, the substance isdissolved in 40 ml of water and 24 ml of 0.1 n sodium hydroxidesolution. It is stirred for 2 hours at room temperature and the solutionis evaporated in a vacuum to dryness. The residue is mixed with 10 ml ofisopropanol, suctioned off, washed with isopropanol and dried at 60° C.in a vacuum. 2.85 g (=86% of theory) is obtained as a white powder witha decomposition point above 250° C.

[0035] Analysis (relative to an anhydrous substance): C 39.28 H 4.76 N10.18 (calculated) C 39.11 H 5.01 N 10.23 (found)

[0036] 4)N³,N⁶-bis(carboxymethyl)-N⁹[3,3-bis(dihydoxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecandioicacid.

[0037] 2.35 g (10 mmol) of 3-amino-1-hydroxypropane-1,1-diphosphonicacid, produced according to DE 2,943,498, is suspended in 200 ml ofwater and mixed with 20 ml of n sodium hydroxide solution to pH9. Then,while keeping the pH constant, 12.10 g (30 mmol) ofN³-(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioicacid is added and it is stirred overnight. Then the solution is broughtto a pH of 12.5 with n sodium hydroxide solution and further stirred for3 hours. After addition of cation exchanger IR 120 to pH 7, the solutionis filtered and chromatographed on silica gel (mobile solvent:butanol/ammonia/ethanol/water=5/2/1/1). The combinedsubstance-containing eluates are evaporated in a vacuum to dryness. 1.3g of a white powder with a melting point of 145° C. is obtained.

[0038] Analysis (relative to an anhydrous substance): C 33.45 H 5.28 N9.18 P 10.15 (calculated) C 33.56 H 5.50 N 9.30 P 10.02 (found)

[0039] 5) Calcium-trisodium salt of DTPA (CaNa₃DTPA)

[0040] 196.6 g (0.5 mol) of DTPA is refluxed with 50 g (0.5 mol) ofcalcium carbonate in 800 ml of water until gas generation is finished.Then, by adding 750 ml of a 2 n sodium hydroxide solution, a neutralsaline solution (pH 7.1) is produced that is evaporated in a vacuum todryness. After drying overnight in a vacuum, 246.2 g of the complex saltis obtained as monohydrate with a melting point near 178-180° C.

[0041] Analysis (relative to an anhydrous substance): C 35.45 H 3.82 N8.86 Ca 8.45 (calculated) C 35.30 H 3.96 N 8.80 Ca 8.39 (found)

Pharmacological Studies

[0042] In pharmacological tests it was established that, despite anabsolute and relatively low dosage, an added portion of free complexingagents or of a weaker metal complex very significantly promoted thecomplete elimination of the heavy metal ion.

[0043] Thus Table 1 shows that by adding only 10% of calcium trisodiumDTPA to the contrast medium, the portion of gadolinium remaining in thebodies of rats one week after i.v. injection of GdDTPA is reduced bygreater than 30%, the concentration in the bones by even about 45%.TABLE 1 ¹⁵³Gd in the rat 7 days after i.v. injection as GdTPA/−dimeglumine in a dose of 0.1 mmol/kg, n = 3, average ± standarddeviation Formulation A Formulation B 0.1 mmol 0.1 mmol GdDTPA + 0.01mmol GdDTPA/kg KG CaNa₃DTPA/kg KG Bones 1.46 ± 0.21 0.79 ± 0.22 (nmol/g)Amount in 0.99 ± 0.24 0.68 ± 0.09 the whole animal (% of the dose)

[0044] The values in Table 2 show that adding only 2 mol % of free DTPA(formulation B) to a contrast medium based on GdDTPA reduces thegadolinium concentration in the liver of rats by more than 50% incontrast to a control with 0.08 mol % of free DTPA (formulation A) up tothe 28th day after injection. TABLE 2 ¹⁵³Gd in the liver of the ratafter i.v. injection of GdDTPA/dimeglumine in a dose of 0.5 mmol/kg;mmol/g net weight of tissue; n = 3; average ± standard deviation. 28 d 2h 6 h 1 d 3 d 7 d 14 d p. inj. Formulation A 0.5 mmol GdDTPA + 20 20 105.6 2.3 1.1 0.4 0.0004 mmol DTPA/kg ±2 ±3 ±3 ±0.9 ±0.6 ±0.3 ±0.1Formulation B 0.5 mmol GdDTPA +22 17 10 5.2 1.6 0.6 0.13 0.01 mmolDTPA/kg ±7 ±1 ±2 ±1.4 ±0.1 ±0.2 ±0.01

[0045] This observed effect of the addition of complexing agents or of aweak metal complex to pharmaceutical preparations based on metalcomplexes was in no way predictable; in fact, it contradictscorresponding in-vitro determinations.

[0046] An assessment of the in-vivo situation is made practicallyimpossible by the fact that all forms of the complexing agent caninteract with ions produced in the body and, on the other hand, offernumerous and in places extremely stable bonding points (proteins;natural complexing agents; anions that form very slightly soluble salts)for heavy metals. In addition, to achieve the object of making availablebetter tolerated diagnostic media, one prejudice of the man of the arthad to be overcome: previously, in the production of contrast mediabased on metal complexes, careful attention was always paid to the factthat there was no excess of either metal ions or free complexing agentsor a weaker com-plex in the solution, since it is known that the freecomplexing agents and the weaker complexes of the complexing agents withmetal ions such as Ca²⁺ are less well tolerated than the strongercomplexes with the heavy metal ions suitable for diagnostics or therapy.

[0047] A surprise of the present invention thus also is in theextraordinarily strong effect of the addition of free complexing agentsor of weak complexes to the metal complex provided for use, e.g., onhuman beings with reference to the stability of the bond of the metaland thus its detoxification and elimination. This advantage is, in viewof the very slow elimination of heavy metals and their inherenttoxicity, of such great significance that for this reason a somewhatreduced acute tolerance of a preparation can possibly be accepted.

[0048] To achieve the desired object, very low concentrations anddosages are typically sufficient. There is an upper limit on the dosageof the complexing agent or of the weaker complexes due to their acutetolerance. A range between 0.01 and 50 mol % (based on the amount of theactual diagnostically or otherwise effective complexing agent) or max.250 mmol/l of the actual diagnostically or otherwise effectivecomplexing agent is suitable. These amounts preferably are between 0.1and 10 mol % or max. 50 mmol/l. These values refer to the total amountsof these additives where mixtures are used.

[0049] In no case is it necessary to add the complexing agent or weakercomplex to the preparations in such a high dose that a relevantreduction in the tolerance of the final preparation occurs compared withthe originally selected diagnostically or therapeutically effectivemetal complex. Further, there is absolutely no necessity for an isolatedor even repeated administration of the complexing agent or weak complex.

[0050] The production of the drug according to the invention occurs in aknown way, e.g., as disclosed in the documents cited above,by—optionally with the addition of additives common in galenicmedicine—mixing the complex compounds suspended or dissolved in anaqueous medium with the complexing or weak metal complex(es) used asadditive and then optionally sterilizing the suspension or solution.Suitable additives are, for example, physiologically safe buffers (e.g.,tromethamine), viscosity-enhancing additives, those that increase theosmolality or, if necessary, electrolytes such as sodium chloride or, ifnecessary, antioxidants such as ascorbic acid.

[0051] If suspensions or solutions of the media according to theinvention in water or of physiological saline solutions are desired forenteral administration or for other purposes, the media can be mixedwith auxiliary agents (e.g., methyl cellulose, lactose, mannitol) and/orsurfactants (e.g., lecithin, Tweens®, Myrj®) and/or aromatics common ingalenic medicine for flavoring (e.g., ethereal oils).

[0052] If suspensions of the complex compounds in water or aphysiological saline solution are desired for oral administration orother purposes, a slightly soluble complex compound is mixed with one ormore auxiliary agents and/or surfactants and/or aromatics common ingalenic medicine for flavoring.

[0053] The drugs according to the invention preferably contain between 1micromol and 1 mol/l of the diagnostically or-therapeutically effectivecomplex salt and are generally dosed in amounts between 0.001 and5.mmol/kg. They are intended for enteral and parenteral application.

[0054] They are used in accordance with the conventional use of theunderlying diagnostic or therapeutic complexes themselves, e.g., asdisclosed in the documents cited above. The additives preferably areco-administered in a single formulation along with the diagnostic ortherapeutic agents but could also be administered in a separateformulation administered at essentially the same time as the formulationof the active complex or sequentially.

[0055] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description; utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0056] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius and unless otherwiseindicated, all parts and percentages are by weight.

[0057] The entire text of all applications, patents and publications, ifany, cited above and below are hereby incorporated by reference.

EXAMPLE 1

[0058] Production of a solution of the di-N-methylglucamine salt of thegadolinium(III)-complex of diethylene-triaminepentaacetic acid (DTPA)with the calcium trisodium salt of DTPA as additive.

[0059] 97.6 g (0.5 mol) of N-methylglucamine is dissolved sterile in 50ml of water. After the addition of 196.6 g (0.5 mol) of DTPA and 90.6 g(0.25 mol) of gadolinium oxide, Gd₂O₃, it is refluxed for 2 hours andthe clear solution is brought to pH 7.2 by adding another 97.6 g (0.5mol) of N-methylglucamine. Next, 24.62 g (50 mmol) of the monohydrate ofthe calcium trisodium salt of DTPA, CaNa₃ DTPA is added and water isadded sterile to produce 1000 ml. The solution is ultrafiltered, placedin an ampule and heat sterilized and is ready for parenteral use.

EXAMPLE 2

[0060] Production of a solution of the di-N-methylglucamine salt of thegadolinium(III) complex of diethylene-triaminepentaacetic acid (DTPA)with the penta-N-methylglucamine salt of DTPA as additive.

[0061] 97.6 g (0.05 mol) of N-methylglucamine is dissolved sterile in500 ml of water. After addition of 196.6 g (0.5 mol) of DTPA and 90.6 g(0.25 mol) of gadolinium oxide, Gd₂O₃, the batch is refluxed for 2 hoursand the clear solution is brought to pH 7.2 by adding another 97.6 g(0.5 mol) of N-methylglucamine. Next, another solution of 197 mg (0.5mmol) of DTPA and 488 mg (2.5 mmol) of N-methylglucamine in 100 ml ofwater is added sterile and water is added sterile to produce 1000 ml.The solution is finally ultrafiltered, placed in an ampule and heatsterilized, and is ready for parenteral use.

EXAMPLE 3

[0062] Production of a solution of the sodium salt of thegadolinium(III) complex of1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA) withthe calcium disodium salt of DOTA as additive.

[0063] 290.3 g (0.5 mol) of the complex salt described in example 11 ofDE 3401052 is dissolved sterile in 700 ml of water. After addition of7.44 g (30 mmol) of the calcium disodium salt of DOTA, water is addedsterile to the neutral solution to produce 1000 ml, it is ultrafiltered,placed in an ampule and heat sterilized.

EXAMPLE 4

[0064] Production of a solution of the lysine salt of thegadolinium(III) complex of DOTA with the zinc disodium salt of DOTA asadditive.

[0065] 80.80 g (0.2 mol) of DOTA (Parish Chemical Comp.) is introducedsterile into a suspension of 36.26 g (0.1 mol) of gadolinium oxide,Gd₂O₃, in 700 ml of water. It is heated with stirring for 20 hours to70° C. and the solution is neutralized by adding an aqueous 20% byweight solution of lysine. Then 10.24 g (20 mmol) of the zinc disodiumsalt of DOTA is added and water is added sterile to the solution toproduce 1000 ml. The solution is ultrafiltered, placed in an ampule andheat sterilized.

EXAMPLE 5

[0066] Production of a solution of the di-N-methylglucamine salt of thegadolinium(III) complex of DTPA with the calcium trisodium salt of DTPAas additive.

[0067] 97.6 g (0.5 mol) of N-methylglucamine is dissolved in 20 l ofwater. After addition of 196.6 g (0.5 mol) of DTPA and 90.6 g (0.25 mol)of gadolinium oxide Gd₂O₃, it is refluxed for 5 hours. 475.4 g (1 mol)of calcium trisodium DTPA, 750 g of mannitol and 100 g of trisodiumcitrate is added, the solution is neutralized with N-methylglucamine andwater is added to produce 50 l. The solution is poured into bottles forenteral application.

EXAMPLE 6

[0068] Production of a solution of the di-N-methylglucamine salt of thegadolinium(III) complex ofN⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid withN⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid as additive.

[0069] 12.58 g (30 mmol) ofN⁶-carboxymethyl-N³,N⁹-bis-(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid is reacted with 5.44 g (15 mmol) of gadolinium oxide, Gd₂O₃, in 500ml of water for 6 hours at 90° C. 12.58 g (30 mmol) ofN⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid, 50 g of mannitol and 8 g of trisodium citrate is added, thesolution is neutralized with N-methylglucamine and water is added toproduce 1000 ml. The solution is poured into bottles for enteral use.

EXAMPLE 7

[0070] Production of a solution of the di-N-methylglucamine salt of thegadolinium(III) complex ofN⁶-carboxymethyl-N³,N⁹-bis(3-oxapentamethylenecarbamoylmethyl)-3,6,9-triazaundecanedioicacid, with the tetrasodium salt ofN³,N⁶-bis-(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid as additive.

[0071] 17.90 g (50 mmol) of1,5-bis-(2,6-dioxomorpholino)-3-azapentane-9-acetic acid is suspended in150 ml of water and dissolved by adding 13.08 ml (150 mmol) ofmorpholine. It is stirred for 16 hours at room temperature and mixedwith 16.57 (50 mmol) of gadolinium(III)-acetate dissolved in 150 ml ofwater. It is further stirred for 2 hours and the solution is treatedsuccessively with the anion exchanger IRA 410 and with the cationexchanger IRC 50.. The neutral solution is then evaporated in a vacuumto dryness. 22.25 g (32.4 mmol) of the desired complex compound isobtained which is dissolved sterile in a solution of 12.65 g (64.8 mmol)of N-methylglucamine in 60 ml of water. 1.66 g (3 mmol) of thetetrasodium salt ofN³,N⁶-bis-(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid is added and water is added sterile to produce 100 ml. The neutralsolution is ultrafiltered, placed in ampules and heat sterilized; it isready for parenteral use.

EXAMPLE 8

[0072] Production of a solution of the disodium salt of themanganese(II) complex of trans-l,2-cyclohexylenediaminetetraacetic acidwith trans-1,2-cyclohexylenediaminetetraacetic acid as additive.

[0073] 395.9 g (500 mmol) of the salt described in example 9 of DE3401052 is suspended sterile in 500 ml of water while being exposed tonitrogen gas. It is mixed with 1.73 g of ascorbic acid and 17.3 g (50mmol) of trans-1,2-cyclohexylenediaminetetraacetic acid, then it isneutralized by adding n sodium hydroxide solution and water is addedsterile to-produce 1000 ml. The solution is filtered sterile usingnitrogen and poured into ampules.

EXAMPLE 9

[0074] Production of a solution of the N-methylglucamine salt of theiron(III) complex of ethylenediamine-N,N′-bis(2-hydroxyphenylaceticacid) (EHPG) with EHPG as additive.

[0075] 36.04 g (0.1 mol) of EHPG is refluxed sterile in 500 ml of waterwith 15.97 g (0.1 mol) of iron(III) oxide, Fe₂O₃, until a solution hasoccurred. 3.604 g (0.01 mol) of EHPG is added and it is brought to pH7.5 by adding N-methylglucamine. Water is added sterile to produce 1000ml and the solution is ultrafiltered, poured into ampules and heatsterilized.

EXAMPLE 10

[0076] Production of an injection solution of the sodium salt of thegadolinium(III) complex ofN³,N⁶-bis(carboxymethyl)-N⁹[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid, withN³,N⁶-bis(carboxymethyl)-N⁹[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid as additive.

[0077] 305.2 g (0.5 mol) ofN³,N⁶-bis(carboxymethyl)-N⁹-[3,3-bis(dihydroxyphosphoryl)3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid is dissolved sterile in 8.5 l of water with addition of 123.6 g(0.25 mol) of gadolinium carbonate, Gd₂(CO₃)₃ at 50° C. Then another30.52 g (0.05 mol) of the complexing agent is added and the pH isbrought to 7.2 during exposure to nitrogen gas by instilling 5 n sodiumhydroxide solution. Water is added sterile to the solution to produce 10l, it is ultrafiltered, poured into ampules and heat sterilized.

EXAMPLE 11

[0078] Production of a solution of the gadolinium(III) complex from theconjugate of DTPA with a monoclonal antibody with the calcium disodiumsalt of DTPA as additive.

[0079] To 20 microliters of a solution of 0.3 mg of monoclonal antibody12 H 12 in 0.05 molar sodium bicarbonate buffer, 1 mg ofN³-(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioicacid is added. After stirring overnight, it is mixed with 2 mg ofgadolinium chloride, GdCl₃, and the solution is dialyzed through a 0.3molar sodium phosphate buffer. Then 1 mg of the calcium trisodium saltof DTPA is added. The sterile filtered solution is poured intoMultivials and lyophilized.

EXAMPLE 12

[0080] Production of a solution of the gadolinium(III) complex of thedextran-DTPA conjugate with the calcium disodium salt of EDTA asadditive.

[0081] A solution of 6.5 g of dextran 10000 is brought to pH 11 with nsodium hydroxide solution. Then 2.12 g of bromocyanogen is added and itis stirred for 30 minutes, and the pH is kept constant by adding morelye. After addition of 20 g of 1-(4-aminobenzyl)DTPA, produced accordingto Can. Pat. 1178951, the solution is further stirred overnight at pH8.5. Then a solution of 8 g of gadolinium chloride, GdCl₃, in 30 ml ofwater is in-stilled, the solution is clarified over activated carbon anddialyzed. The dialyzate is mixed with 3 g of the calcium disodium saltof ethylenediaminetetraacetic acid (EDTA), filtered sterile, poured intoMultivials and lyophilized. The lyophilizate contains about 10% ofcomplex bonded gadolinium.

[0082] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0083] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. In a pharmaceutical agent comprising a metalcomplex, useful for NMR, X-ray, ultrasound or radio-diagnostics orradiotherapy, the improvement wherein said agent further comprises ametal complexing agent, a weak metal complex or a mixture thereof.
 2. Anagent of claim 1, comprising said metal complexing agent.
 3. An agent ofclaim 1, comprising said weak metal complex, wherein said metal isphysiologically acceptable and the binding constant of said weak metalcomplex is lower than that of said diagnostically or therapeuticallyuseful metal complex.
 4. An agent of claim 1, wherein the metal of saidweak metal complex is calcium, magnesium, zinc or iron.
 5. An agent ofclaim 2, wherein the complex portion of all of said complexes andcomplexing agents is, independently., e.g., ethylenediaminetetraaceticacid. (EDTA), diethylenetriaminepentaacetic acid (DTPA),1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA),trans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid,N⁶-carboxymethyl-N³,N⁹-[2,3-dihydroxy-N-methylpropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid,N⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid,N³,N⁶-bis(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid orN³,N⁶-bis(carboxymethyl)-N⁹-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]-3,6,9-triazaundecanedioicacid.
 6. An agent of claim 3, wherein the complex portion of all of saidcomplexes and completing agents is, independently, e.g.,ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaaceticacid (DTPA), 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid(DOTA), trans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid,N⁶-carboxymethyl-N³,N⁹-[2,3-dihydroxy-N-methylpropylcarbamoylmethyl]-3,6,9-triazaundecanedioicacid,N⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid,N³,N⁶-bis(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid orN³,N⁶-bis(carboxymethyl)-N⁹-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]3,6,9-triazaundecanedioicacid.
 7. An agent of claim 1, wherein the total amount of saidcomplexing agent and/or weak metal complex is 0.01.-50 mol % based onthe amount of said diagnostically or therapeutically effective complex,up to a maximum of 250 mmol/l of said effective complex.
 8. An agent ofclaim 1, wherein the total amount of said complexing agent and/or weakmetal complex is 0.1-10 mol % based on the amount of said diagnosticallyor therapeutically effective complex, up to a maximum of 50 mmol/l ofsaid effective complex.
 9. An agent of claim 1, further comprising apharmaceutically acceptable carrier.
 10. An agent of claim 1, comprisingthe di-N-methylglucamine salt of the gadolinium(III) complex of DTPA andthe calcium trisodium salt of DTPA.
 11. An agent of claim 1, comprisingthe di-N-methylglucamine salt of the gadolinium(III) complex of DTPA andthe penta-N-methylglucamine salt of DTPA.
 12. An agent of claim 1,comprising the sodium salt of the gadolinium(III) complex of1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA) andthe calcium disodium salt of DOTA.
 13. An agent of claim 1, comprisingthe lysine salt of the gadolinium(III) complex of DOTA and the zincdisodium salt of DOTA.
 14. An agent of claim 1, comprising thedi-N-methylglucamine salt of the gadolinium(III)-complex ofN⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid andN⁶-carboxymethyl-N³,N⁹-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid.
 15. An agent of claim 1, comprising the di-N-methylglucamine saltof the gadolinium(III) complex of N⁶-carboxymethyl-N³ ,N⁹-bis(3-oxapentamethylene-carbamoylmethyl)-3,6,9-triazaundecanedioic acid andthe tetrasodium salt ofN³,N⁶-bis-(carboxymethyl)-N⁹-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioicacid.
 16. An agent of claim 1, comprising the disodium salt of themanganese(II) complex of trans-1,2-cyclohexylenediaminetetraacetic acidand trans-1,2-cyclohexylenediaminetetraacetic acid.
 17. An agent ofclaim 1, comprising the N-methyl-glucamine salt of the iron(III) complexof ethylenediamine-N-N′-bis(2-hydroxyphenylacetic acid) (EHPG) and EHPG.18. An agent of claim 1, comprising the sodium salt of thegadolinium(III) complex ofN³,N⁶-bis(carboxymethyl)-N⁹-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedioic acid andN³,N⁶-bis(carboxymethyl)-N⁹-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedioic acid.
 19. An agent of claim1, comprising the gadolinium(III) complex of the conjugate of DTPA witha monoclonal antibody and the calcium disodium salt of DTPA.
 20. Anagent of claim 1, comprising the gadolinium(III) complex of thedextran-DTPA conjugate and the calcium disodium salt of EDTA.
 21. In amethod of performing an NMR, X-ray, ultrasound or radio-diagnosis orimage, or radiotherapy of a patient, comprising administering aneffective amount of a metal complex, the improvement wherein there iscoadministered a metal complexing agent, a weak metal complex or amixture thereof.